1,2,4a,5,6,8,9,14,14a,14b-decahydrobenz(a)indolo(2,3-g)quinolizin-3(4h)-ones

ABSTRACT

COMPOUNDS OF THE FORMULA ARE DISCLOSED:   3-(O=),9-R,X-1,2,3,4,4A,5,6,8,9,14,14A,14B-DODECAHYDRO-   BENZ(A)INDOLO(2,3-G)QUINOLIZINE   WHEREIN X IS HYDROGEN, LOWER ALKYL, LOWER ALKOXY, HALOGEN, AMINO, N,N-DISUBSTITUTED AMINO, ETHERIFIED MERCAPTO, NITRO AND HYDROXYL; AND R IS HYDROGEN, LOWER ALKYL, ARALKYL SUBSTITUTED ARALKYL AND ACYL. THESE COMPOUNDS ARE PREPARED BY THE CYCLIZATION OF A 1,2,3,4-TETRAHYDRO-1(INDOL-3-YLMETHYL)-6-METHOXYISOQUINOLINE WITH FORMALDEHYDE TO GIVE A HEXAHYDRO-3-METHOXYBENZE(A)INDOLO(2,3-G)QUINOLIZINE, FOLLOWED BY REDUCTION AND HYDROLYSIS RESPECTIVELY. THESE COMPOUNDS ARE USEFUL AS ANTI-HYPERTENSIVE AGENTS.

United States Patent 3,772,306 1,2,4a,5,6,8,9,14,14a,14b-DECAHYDROBENZ[a] INDOLO[2,3-g]QUINOLIZIN-3(4H)-0NES Glenn C. Morrison, Dover, and John Shave], Jr., Mendham, N.J., assignors to Warner-Lambert Company,

Morris Plains, NJ. No Drawing. Filed Nov. 26, 1971, Ser. No. 202,570 Int. Cl. C07d 39/00 U.S. Cl. 260288 R 4 Claims ABSTRACT OF THE DISCLOSURE Compounds of the formula are disclosed:

bi/b wherein X is hydrogen, lower alkyl, lower alkoxy, halogen, amino, N,N-disubstituted amino, etherified mercapto, nitro and hydroxyl; and R is hydrogen, lower alkyl, aralkyl, substituted aralkyl and acyl.

These compounds are prepared by the cyclization of a l,2,3,4-tetrahydro-1(indol 3 ylmethyl)-6-methoxyisoquinoline with formaldehyde to give a hexahydro-3-methoxybenz[a]indolo[2,3-g]quinolizine, followed by reduction and hydrolysis respectively.

These compounds are useful as anti-hypertensive agents.

The present invention is concerned with l,2,4a,5,6,8,9, 14,14a,14b decahydrobenz[a]indolo[2,3 glquinolizin- 3(4H)-ones having the following structural formula:

where X=hydrogen, lower alkyl such as methyl, ethyl, isobutyl, hexyl, and the like, lower alkoxy such as methoxy and ethoxy, halogen such as fluorine, chlorine and bromine, amino, N,N-disubstituted amino and the like, etherified mercapto such as methylmercapto and ethylmercapto, nitro and hydroxyl.

where R=hydrogen, lower alkyl such as methyl, ethyl, isobutyl, hexyl and the like, aralkyl such as phenethyl, substituted aralkyl such as chlorobenzyl, and acyl such as acetyl, benzoyl and the like.

about 1 mg. per kg. to 10 mg. per kg. administered by injection to dogs significantly reduces the arterial pressure.

These compounds are indicated in conditions associated with high blood pressure. Generally speaking, a dose of 10-100 mg. based on the body weight in several divided doses as prescribed to produce the desired hypotensive activity.

a -In order to use these compounds, they are formulated by pharmaceutically acceptable vehicles such as peanut oil, sesame oil and the like into dosage forms suitable for parenteral administration.

, The compounds of this invention are prepared by the cyclization of a l,2,3,4-tetrahydro-l(indol-3-ylmethyl)-6- methoxyisoquinoline with formaldehyde to give a hexahydro-3-methoxybenz[a]indolo[2,3-g]-quinolizine of the formula:

OCH:

N is The reduction of (1) aifords a dihydro derivative of the formula:

OCH:

mula:

M A/ J In order to further illustrate the practice of this invention, the following examples are included.

EXAMPLE 1 O CH:

,9,14,14a-hexahydro-3-methoxybenz[a]indolo [2,3-g] quinolizine To a solution of 29.2 g. of 1,2,3,4-tetrahydro-l-(indol- 3-ylmethyl)-6-methoxyisoquinoline and 3.96 ml. of 37% formaldehyde solution in 2 l. of 3% acetic acid was added 1 l. of an 1 N sodium hydroxide solution over a 5 hour interval. Filtration of the reaction mixture gave a solid which after recrystallization from benzene afforded 22.0 g. (72%) of a solid, M.P. 201.5-203.5. Recrystallization from Skellysolve B gave an analytical sample, M.P. 202-2035".

Analysis.Calcd. for C H N O (percent): C, 78.92; H, 6.62; N, 9.20. Found (percent): C, 78.95; H, 6.60; N, 9.15.

EXAMPLE 2 1,4,5,6,8,9,14,14a-octahydro-3-methoxybenz [a] indolo [2,3-g] quinolizine To a solution of 15.0 g. of 5,6,8,9,14,14a-hexahydro- 3-methoxybenz[a]indolo[2,3-g]quinolizine in 500 ml. of tetrahydrofuran was added 1 l. of liquid ammonia. To the resulting solution was added 7.2 g. of sodium and 32 ml. of t-butanol in six equal portions over a 5-hr. period. The unreacted sodium was destroyed with methanol and the ammonia was allowed to evaporate. The residue was poured into 1500 ml. of water. A solid was deposited which after slurring with 750 ml. of hot isopropyl ether gave 13.9 g. (92%) of a solid, M.P. 212214.

Analysis.Calcd. for C H N O (percent): C, 78.40; H, 7.24; N, 9.14. Found (percent): C, 78.38; H, 7.40; N, 9.16.

O CH:

EXAMPLE 3 1,5,6,8,9,14,14a,14b-octahydrobenz[a]indolo[2,3-g] quinolizin-3 (2H) -one washed with water, dried over sodium sulfate, and the solvent was removed. Trituration of the residue with acetonitrile afiorded 4.6 g. (48%) of a crystalline solid, M.P. 2l7-224. Further recrystallization gave an analytical sample, M.P. 219-220.

Analysis.Calcd. for C H N O (percent): C, 78.05; H, 6.90; N, 9.58. Found (percent): C, 77.82; H, 6.99; N, 9.41.

EXAMPLE 4 c y i reduction N 1,4,4a,5,6,8,9,14,14a,l4b-decahydrobenz[a]indo1o [2,3-g1quinolizin-3 (2H)-one To a solution of 1.0 g. of l,5,6,8,9,14,l4a,14b-octahy drobenz[a]indolo[2,3-g]quinolizin-3(2H)-one and 6 ml. of 3 N hydrochloric acid in 150 ml. of methanol was added 500 mg. of 10% palladium on charcoal and the mixture was hydrogenated. After hydrogen uptake had ceased the catalyst was removed by filtration. On concentration of the solution there was deposited a solid. The solid was shaken with 10% sodium hydroxide solution and methylene chloride. The methylene chloride layer was Washed with water, dried over sodium sulfate, and the solvent was removed. Crystallization of the residue from ether afforded 0.33 g. (33%) of a crystalline solid, M.P. 133-134. Recrystallization from isopropyl ether gave an analytical sample, M.P. 144-145 Analysis.-Calcd. for C H N O (percent): C, 77.52; H, 7.53; N, 9.52. Found (percent): C, 77.42; H, 7.57; N, 9.27.

EXAMPLE 5 1,4,4a,5,6,8,9, 14, 14a, 14b-decahydrobenz [a] indolo [2,3-g1quinolizin-3 (2H)-one To a solution of 3.0 g. of 1,5,6,8,9,14,14a,l4b-octahydrobenz[a]indolo[2,3-g]quinolizin-3(2H)-one in ml. of tetrahydrofuran was added 250 ml. of ammonia. Then 0.12 g. of lithium was added and the mixture stirred for 1 hr. The excess lithium was destroyed by the addition of 0.19 g. of ammonium chloride over a 1 hr. interval and the ammonia was allowed to evaporate. 0n the addition of 700 ml. of water, there was deposited a solid which after recrystallization from benzene gave 1.8 g. (60%) of a crystalline solid, M.P. 288-293". Further recrystallization gave an analytical sample, M.P. 300-304.

Analysis.Calcd. for C H N O (percent): C, 77.52; H, 7.53; N, 9.52. Found (percent): C, 77.25; H, 7.60; N, 9.67.

We claim:

1. 1,4,4a,5,6,8,9,14,14a,14b decahydrobenz[a]indolo [2,3-g] quinolizin-3 (2H -one.

2. 5,6,8,9,l4,14a hexahydro-3-methoxybenz[aJindol [2,3-g]quinolizine.

3. 1,4,5,6,8,9,14,14a-octahydro 3 methoxybenz[a] indolo[2,3-g]quinolizine.

4. 1,5,6,8,9,14,14a,14b octahydrobenzfaJindolo[2,3-g] OTHER REFERENCES quinolizin-3(2H)-one.

References Cited 4920-3 (1952)' UNITED STATES PATENTS 5 DONALD G. DAUS, Primary Examiner 3,480,633 11/1969 Schut 260-288 R 3,492,303 1/1970 Shavel et a1 260-288 R 3,518,271 6/ 1970 Shavel et a1. 260-288 R 260-283 S, 287 R, 999

3,524,857 8/1970 Shavel 260-288 R Boekelheide et aL: Jour. Am. Chem. Soc., vol. 74, pp. 

